This application claims benefit of Indian Provisional Patent Application No. 3196/CHE/2013, filed Jul. 17, 2013, entitled “Azaindole Compounds. Synthesis Thereof, and Methods of Using the Same,” and also claims benefit of a second and updated provisional application having the same serial number (3196/CHE/2013) and a filing date of Apr. 30, 2014, the entire contents of both of which are hereby incorporated by reference.
Tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide, despite having an effective and economical quadruple drug therapy regimen, put in place 40 years ago (Raviglione, M. et al. Lancet 379, 1902-1913 (2012); World Health Organization. Global Tuberculosis Report (2012)). It is gratifying to see US Food and Drug Administration (FDA)'s recent accelerated approval of Janssen's Sirturo (bedaquiline) for multidrug-resistant tuberculosis (MDR-TB), putting an end Co four-decade-long lull for a new TB drug with novel mechanism of action (Cohen, J. Science 339, 130-131 (2013)). However, the impact of Sirturo on disease landscape and patient's lives needs to be seen; in the context of associated safety risks and the burden of post marketing studies.
The nitro-benzothiazinones (BTZs) and related compounds are known to inhibit decaprenylphosphoryl-β-D-ribose2′-epimerase1 (DprE1) involved in the conversion of decaprenylphosphoryl-β-D-ribose (DPR) to decaprenylphosphoryl-β-D-arabinofuranose (DPA), a precursor of mycobacterial cell wall arabinan (Trefzer, C. et al. J. Am. Chem. Soc. 132, 13663-13665). This reaction is catalysed by a heteromeric enzyme decaprenyl-phospho-ribose 2′-epimerase (DprE), which occurs via a sequential oxidation-reduction mechanism involving an intermediate (decaprenylphosphoryl-2-keto-β-D-erythro-pentofuranose, DPX). This enzyme is composed of two proteins encoded by the dprE1 and dprE2 genes. DprE1 enzyme is the FAD-containing oxidoreductase, while DprE2 is the NADH-dependent reductase (Mikusova, K. et al. J. Bacteriol. 187, 8020-8025 (2005); Makarov, V. et al. Science 324, 801-804 (2009)).
The identification of BTZ043 as a covalent inhibitor of DprE1 with potent antimycobacterial activity confirms the validity of this target for a novel TB therapy (Science 324, 801-804 (2009)). However, it remains to be understood whether non-nitro inhibitors of DprE1 will lead to efficacy in vivo? Additionally, is nanomolar cellular activity essential for in vivo efficacy? Greater understanding in relation to these aspects of DprE1 inhibition will significantly influence future TB drug discovery efforts directed at this target. Thus, a need exists in the art for additional compounds that target DprE1.